Alzheimer's disease (AD) is the most common cause of dementia worldwide. The exponential rise in the number of cases of AD in the past and the future projections over next few decades is anticipated to result in great pressure on the social and health-care systems of developed and developing economies alike. AD also imposes tremendous emotional and financial burden to the patient's family and community.
The current list of approved cognition enhancing drugs for AD is not long and historically been focused on acetylcholinesterase inhibitors (donepezil, rivastigmine and galantamine). These drugs act by inhibiting the hydrolysis of acetylcholine (ACh) into acetate and choline by targeting acetylcholinesterase (AChE) enzyme. Increasing the ACh levels in the synapse can stimulate cholinergic receptors and promote memory function. Although acetylcholinesterase inhibitors (AChEIs) can temporarily delay the progression of cognitive decline in AD, their effects are modest. ACh being present both in the central and peripheral nervous system, AChEIs produce several undesirable side effects such as gastrointestinal disturbances, bradycardia and excessive salivation that are associated with an action on peripheral muscarinic cholinergic receptors (Expert Opinion on Drug Safety, 3, 2004, 425-440). The limitation of AChE inhibitor class of drugs is that they are poorly tolerated, their efficacy is not sustained and they require constant dose-titration as the disease progresses (Cochrane Database Systematic Reviews, 2006, CD005593) which lead to significant patient noncompliance. The incidence and the severity of these side effects increase with the dose amount and in general more pronounced at the initiation of the treatment or after dose increase. Hence there is an unmet need of alternate therapy for treating cognition disorders.
The H3R is a G protein-coupled receptor (GPCR), mainly expressed in the anterior part of the cortex, hippocampus and the striatum. H3Rs function as both autoreceptors and heteroreceptors. It modulates the synthesis and release of several neurotransmitters which play an important role in cognition, mood and sensory gating. Preliminary literature reports suggest that H3R antagonists/inverse agonist may have promising utility for the treatment of various CNS disorders including AD, schizophrenia, attention-deficit hyperactivity disorder (ADHD), epilepsy, narcolepsy, neuropathic pain and metabolic disorders. Antagonism of this receptor by several investigational compounds has been shown to improve learning and memory in animal models.
The patent applications, WO2015032966, WO2014136075 and US20150080379 disclose the combination of H3R antagonist and acetylcholinesterase inhibitors for the treatment of AD. However, none of these combinations are approved for the treatment of AD. As the treatment of AD is chronic in nature, there is a desperate unmet medical need for better and safer treatment options. The current approved treatment for AD includes use of AChEI or NMDA antagonist alone or the combination of AChEI and NMDA antagonist. However, there remains the need for the new drugs/combination to treat the patients with AD. A therapeutic strategy eagerly sought for AD patients is to target an improvement with an adjunct to existing therapies that would bring additional relief for patients, lower the burden on the caregiver and allow the patient to enjoy a better quality of life without the need for institutional care and/or hospitalization.
Since the cause and development of the dementia depend on the different mechanisms, it may be an advantageous to use the combination of drugs working in different mechanism for the treatment of AD. This may in turn help to reduce side effects with better patient compliance and thus can be administered over a long period.
The compounds of the present invention are H3R inverse agonists with high affinity and very high selectivity over closely related receptor subtypes and improve learning and memory in animals. The H3R inverse agonist compounds mentioned here are described in U.S. Pat. No. 9,079,888B2 which is incorporated by reference. The preparation of these compounds is given in the said patent.
The instant invention provides H3R inverse agonist or the pharmaceutically acceptable salt(s) thereof, which may enhance the cognitive function of patients on treatment with acetylcholinesterase inhibitors. The present invention is based on the finding that the instant compounds with H3R inverse agonist affinity enhance and also prolong the effect of the acetylcholinesterase inhibitors. The combination of the instant invention demonstrates a synergistic effect in their pharmacological activity. Such combined administration of H3R inverse agonist and acetylcholinesterase inhibitor can result in beneficial effect to improve the therapeutic efficacy in humans.